Gastrointestinal motility regulates the orderly movement of ingested material through the gut to insure adequate absorption of nutrients, electrolytes and fluids. Appropriate transit through the esophagus, stomach, small intestine and colon depends on regional control of intraluminal pressure and several sphincters that regulate forward movement and prevent back-flow of gastrointestinal contents. The normal gastrointestinal motility pattern may be impaired by disease, surgery or by adverse reaction to drug treatment for non-gastrointestinal disease.
Motilin is a 22 amino acid peptide that is secreted from enterochromaffin cells in the small intestine into the bloodstream, binds to a G-protein coupled receptor, GPR38, and is involved in the normal regulation of coordinated motility of the gastrointestinal tract (J. C. Brown, M. A. Cook, J. R. Dryburgh; Can. J. Biochem., 1973, 51:533). There is also evidence that the motilin receptor is expressed in the colon and motilin has been shown to increase cell calcium and to stimulate contraction of human colonic smooth muscle (G. Van Assche, I. Depooŕtere, T. Thijs, L. Missiaen, F. Pennenckx, H. Takashi, K. Geboes, J. Janssens, and T. L. Peeters, Neurogastroentero. Mot. 2001, 13:27-35). Erythromycin is a motilin agonist and is used therapeutically to increase the rate of gastric emptying (T. Peeters, G. Matthijs, I. Depoortere, T. Cachet, J. Hoogmartens, G. Vantrappen, Am. J. Physiol. Gastrointest Liver Physiol., 1989, 257, G470-G474; J. Janssens, T. L. Peeters, G. Vantrappen, J. Tack, J. L. Urbain, M. DeRoo, E. Muls, R. Bouillon, N. Engl. J. Med. 1990, 322, 1028-1031). In addition, motilin peptide analogs and motilides have been shown to stimulate contraction in antral and colonic gastrointestinal muscle strips (L. Thielemans, I. Depoortere, J. V. Broeck, and T. L. Peeters, Biochem. Biophys. Res. Comm. 2002, 293, 1223-1227). Therefore, it is expected that potent motilin agonists will act as a prokinetic agent and be useful for the treatment of delayed gastric emptying (gastroparesis) in normal and diabetic patients, postoperational ileus, irritable bowel syndrome, functional dyspepsia, chronic constipation, gastroesophogeal reflux disease or other conditions where motility is delayed. It will also be useful for treatment of colonic motility disorders including colonic hypomotility. Moreover, motilin agonists will promote gastrointestinal motility in a coordinated manner, thereby avoiding some common side effects associated with other prokinetic agents, such as nausea, constipation, and diarrhea.
Other examples of disorders whose symptoms include impaired gastrointestinal motility are anorexia, gall bladder stasis, postoperative paralytic ileus, scleroderma, intestinal pseudoobstruction, gastritis, emesis, and chronic constipation (colonic inertia). These gastrointestinal disorders are generally treated with prokinetic agents that enhance propulsive motility and thus could be treated with a motilin agonist.
U.S. Pat. No. 6,117,896 to Qabar et al. discloses β-sheet mimetics which have the structure
wherein
A is selected from —(═O)—, —(CH2)0-4—, —C(═O)(CH2)1-3—, —(CH2)1-20— and —(CH2)1-2S—;
B is selected from N and CH;
C is selected from —C(═O)—, —(═O)(CH2)1-3—, —(CH2)0-3—, —O—, —S—, —O—(CH2)1-2— and —S(CH2)1-2—;
D is selected from N and C(R4);
E is selected from

F is an optional carbonyl moiety;
R1 and R4 are independently selected from amino acid side chain moieties and derivatives thereof;
R2 and R2′ represent one or more ring substituents individually selected from an amino acid side chain moiety and derivatives thereof, or R2 taken together with C or Y forms a fused substituted or unsubstituted homocyclic or heterocyclic ring;
R3 is selected from an amino acid side chain moiety and derivatives thereof, or taken together with C forms a bridging moiety selected from —(CH2)1-2—, —O— and —S—;
Y and Z represent the remainder of the molecule; and
any two adjacent CH groups of the bicyclic ring may form a double bond.
In one embodiment, R2 taken together with C forms a heterocyclic fused ring as represented by
wherein A, B, C, D, E, R2, R2′, R3 and Y are as defined above, and R′ is one or more optional ring substituents.
In one aspect of structure (X), R2 and C taken together form a fused five-, six-, seven- or eight-membered ring as represented by structure (Xb):
wherein A, B, C, D, E, Y, R2, R2′, R3 and R′ are as defined above, and X is selected from —C(═O)—, —NH—, —NR′—, —O— and —S—.